The proposed research seeks a better understanding of the mechanisms of aging. Cultured mammalian cells and a small nematode that contains only about 800 somatic cells in the adult form will be used as model systems to avoid the complexities associated with research involving whole mammals. Both intracellular and extracellular controls over the loss of reproductive capacity associated with aging in cultured diploid cells will be investigated. Ultrastructural studies, together with experiments seeking to recombine nuclei and cytoplasms from young and old cells, will be used to evaluate whether cellular senescence is determined by the nucleus or the cytoplasm, or both. Nutrient and environmental conditions that modify aging in vitro will be analyzed and mechanisms of action of factors found to alter the process will be investigated. Clonal culture techniques will be used to evaluate changes in growth potential of individual cells from aging animals. The small nematode Caenorhabditis elegans, which has a short lifespan and well defined genetics, will be used to investigate genetic control of aging. Precise morphological and biochemical studies of aging in the nematodes will also be undertaken, together with an analysis of the environmentally induced changes that prolong lifespan when Dauer larvae are formed. The proposed research seeks to understand aging in terms of molecular events occurring within and among the individual cells of the organism with the conviction that such knowledge will greatly improve prospects for ultimate control of the diseases of old age by medical science.